Titanium implant surfaces free from alpha case and with enhanced osteoinduction

ABSTRACT

An orthopedic implant having a titanium or titanium alloy body with a plurality of surfaces. The orthopedic implant is produced according to a process comprising the steps of: (a) additively building the orthopedic implant; and then (b) mechanically, chemically, or mechanically and chemically eroding one or more surfaces of the orthopedic implant to (i) remove alpha case from, and (ii) impart an osteoinducting roughness including micro-scale structures and nano-scale structures into, the one or more surfaces.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 62/370,459 filed on Aug. 3, 2016, the contents ofwhich are incorporated in this document by reference.

FIELD OF THE INVENTION

The invention relates generally to the field of orthopedic implants. Inparticular, the invention relates to metal surfaces for orthopedicimplants, which upon implantation within the body stimulate mesenchymalstem cells to differentiate into preosteoblasts, and stimulatepreosteoblasts to mature into osteoblasts, thereby facilitating new bonegrowth. The surfaces are prepared by a combination of an additivemanufacture process followed by secondary processing. The surfaces arefree from alpha case.

BACKGROUND OF THE INVENTION

Various publications, including patents, published applications,technical articles, and scholarly articles are cited throughout thespecification. Each of these cited publications is incorporated byreference herein, in its entirety and for all purposes.

Various orthopedic implants are used to correct skeletal defects. Inmany cases, integration of the implant with adjacent bone is desired,though not easily achieved. For example, it is known that certainpolymeric materials such as polyether ether ketone (PEEK) commonly usedin orthopedic implants are incapable of integrating with bone. Even formetals such as titanium alloys that are capable of integrating withbone, smooth surfaces provide for slow and poor integration. Moreover,integration surfaces on orthopedic implants that are adorned with teeth,spikes, grooves, and other projecting surfaces can actually impede oravoid bone integration.

Where integration is desired, the rate of integration directly relatesto the overall well-being of the patient. The faster the integration,the faster the surgically repaired area heals, and the faster thepatient can resume their lifestyle formerly impeded by the conditionrequiring orthopedic intervention. Accordingly, it is highly desiredthat integration occur between the orthopedic implant and adjacent bone.Therefore, there remains a need in the art for integration surfaces thatcan achieve rapid and high-quality osseointegration.

SUMMARY OF THE INVENTION

To meet this and other needs, and in view of its purposes, the inventionfeatures osteoinducting surfaces of an orthopedic implant, includingbone-contacting and free surfaces. These osteoinducting surfaces areproduced according to a process comprising additively manufacturing anorthopedic implant having one or more free surfaces and having one ormore bone-contacting surfaces adapted to be placed in contact with bone,and then mechanically, chemically, or mechanically and chemicallyeroding the one or more bone-contacting surfaces, and, optionallymechanically, chemically, or mechanically and chemically eroding one ormore of the one or more free surfaces, to remove alpha case and impartan osteoinducting roughness comprising micro-scale structures andnano-scale structures into the mechanically, chemically, or mechanicallyand chemically eroded surfaces. One or more of the one or morebone-contacting surfaces and free surfaces may comprise a macro-scaleroughness. In preferred aspects, following the additive manufacturing,the process comprises mechanically eroding and then chemically erodingthe one or more bone-contacting surfaces, and, optionally mechanically,chemically, or mechanically and chemically eroding one or more of theone or more free surfaces, to impart the osteoinducting roughness. Thus,in some preferred aspects where one or more of the one or more freesurfaces are eroded, some of the free surfaces are eroded and some ofthe free surfaces are not eroded.

Bone-contacting surfaces and free surfaces produced according to thisprocess significantly enhance, facilitate, and/or upregulate, includingthe rate and extent thereof, one or more of osteoinduction,osteogenesis, mesenchymal stem cell expression of alkaline phosphatase,preosteoblast expression of osterix, and osteoblast expression ofosteocalcin. Such enhancement, facilitation, and/or upregulation occurswhen such surfaces are brought in contact with bone or are brought incontact with mesenchymal stem cells. Such contact may be in vitro, or invivo or in situ. The enhancement in one or more of osteoinduction,osteogenesis, mesenchymal stem cell expression of alkaline phosphatase,preosteoblast expression of osterix, and osteoblast expression ofosteocalcin attained by surfaces produced according to this process issignificantly greater than the osteoinduction, osteogenesis, mesenchymalstem cell expression of alkaline phosphatase, preosteoblast expressionof osterix, and/or osteoblast expression of osteocalcin attained byother types of surfaces of orthopedic implants when such other types ofsurfaces are brought in contact with bone or are brought in contact withmesenchymal stem cells, which contact may be in vitro, or in vivo or insitu. In some aspects, such other types of surfaces are devoid of anosteoinducting roughness comprising micro-scale structures andnano-scale structures, for example, surfaces that have not been treatedby mechanical and/or chemical erosion to impart an osteoinductingroughness comprising micro-scale structures and nano-scale structures.

In some aspects, the one or more bone-contacting surfaces producedaccording to the process, when placed in contact with bone,significantly enhance osteoinduction relative to the osteoinduction froma comparative bone-contacting surface comprising a macro-scale roughnessand comprising an osteoinducting roughness comprising micro-scalestructures and nano-scale structures produced by mechanically andchemically eroding a bulk substrate, when the comparative surface isplaced in contact with bone. In some aspects, the one or morebone-contacting surfaces produced according to the process, when placedin contact with bone, significantly enhance osteogenesis relative to theosteogenesis from a comparative bone-contacting surface comprising amacro-scale roughness and comprising an osteoinducting roughnesscomprising micro-scale structures and nano-scale structures produced bymechanically and chemically eroding a bulk substrate, when thecomparative surface is placed in contact with bone. In some aspects, theone or more bone-contacting surfaces produced according to the process,when placed in contact with bone, significantly enhance the level ofexpression of alkaline phosphatase by mesenchymal stem cells relative tothe level of expression of alkaline phosphatase by mesenchymal stemcells from a comparative bone-contacting surface comprising amacro-scale roughness and comprising an osteoinducting roughnesscomprising micro-scale structures and nano-scale structures produced bymechanically and chemically eroding a bulk substrate, when thecomparative surface is placed in contact with bone. In some aspects, theone or more bone-contacting surfaces produced according to the process,when placed in contact with bone, significantly enhance the level ofexpression of osterix by preosteoblasts relative to the level ofexpression of osterix by preosteoblasts from a comparativebone-contacting surface comprising a macro-scale roughness andcomprising an osteoinducting roughness comprising micro-scale structuresand nano-scale structures produced by mechanically and chemicallyeroding a bulk substrate, when the comparative surface is placed incontact with bone. In some aspects, the one or more bone-contactingsurfaces produced according to the process, when placed in contact withbone, significantly enhance the level of expression of osteocalcin byosteoblasts relative to the level of expression of osteocalcin byosteoblasts from a comparative bone-contacting surface comprising amacro-scale roughness and comprising an osteoinducting roughnesscomprising micro-scale structures and nano-scale structures produced bymechanically and chemically eroding a bulk substrate, when thecomparative surface is placed in contact with bone.

The step of additively manufacturing the orthopedic implant may compriseadditively manufacturing the orthopedic implant with electron beammelting (EBM). The step of additively manufacturing the orthopedicimplant may comprise additively manufacturing the orthopedic implantwith selective laser sintering, including, for example, direct metallaser sintering (DMLS). The step of additively manufacturing theorthopedic implant may comprise additively manufacturing the orthopedicimplant with selective laser melting, including, for example,laserCUSING™. The step of additively manufacturing the orthopedicimplant may comprise additively manufacturing the orthopedic implantwith fused deposition modeling (FDM), direct metal deposition, laserEngineered Net Shaping (LENS), wire-based directed energy deposition, orany other method using an energy source to melt. The additivemanufacture process may further comprise hot isostatic pressing (HIP) orstress-relieving the orthopedic implant following the step of additivelymanufacturing the orthopedic implant.

The orthopedic implant preferably comprises a metal or ceramic. Themetal may comprise a cobalt chromium alloy, an alloy of titanium, analloy of titanium, aluminum, and vanadium, an alloy of titanium andnickel, nitinol, or stainless steel.

The invention also features orthopedic implants, which implants compriseone or more bone-contacting surfaces and one or more free surfaces thatare produced according to any of the processes described or exemplifiedherein. Surfaces on these implants that are processed by mechanicalerosion, chemical erosion, or both mechanical and chemical erosioninclude an osteoinducting roughness comprising micro-scale structuresand nano-scale structures that significantly enhance, facilitate, and/orupregulate osteoinduction, including the rate and extent thereof, whensuch surfaces are brought in contact with bone or are brought in contactwith mesenchymal stem cells, for example, following implantation of theimplants within the body.

The invention still further features an orthopedic implant having atitanium or titanium alloy body with a plurality of surfaces. Theorthopedic implant is produced according to a process comprising thesteps of: (a) additively building the orthopedic implant; and then (b)mechanically, chemically, or mechanically and chemically eroding one ormore surfaces of the orthopedic implant to (i) remove alpha case from,and (ii) impart an osteoinducting roughness including micro-scalestructures and nano-scale structures into, the one or more surfaces.Alternatively, the process comprises the steps of (a) additivelybuilding the orthopedic implant having one or more free surfaces andhaving one or more bone-contacting surfaces adapted to be placed incontact with bone, at least the one or more bone-contacting surfaceshaving a macro-scale roughness that inhibits movement of the orthopedicimplant when the bone-contacting surfaces are placed in contact withbone; and then (b) sequentially mechanically and chemically eroding oneor more of the one or more free surfaces and the one or morebone-contacting surfaces to (i) remove alpha case from, and (ii) impartan osteoinducting roughness including micro-scale structures andnano-scale structures into, one or more of the one or more free surfacesand the one or more bone-contacting surfaces.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary, but are notrestrictive, of the invention.

BRIEF DESCRIPTION OF THE DRAWING

The invention is best understood from the following detailed descriptionwhen read in connection with the accompanying drawing. Included in thedrawing are several figures, as summarized below.

FIG. 1A shows scanning electron microscope (SEM) images of additivelymanufactured surfaces, including surface 20A which is a DMLS-producedsurface that was subject to stress-relief but no erosion and surface 22Awhich is a DMLS-produced surface that was subject to stress-relief andmechanical and chemical erosion;

FIG. 1B shows SEM images of additively manufactured surfaces, includingsurface 20B which is an EBM-produced surface that was subject to hotisostatic pressing (HIP) but no erosion and surface 22B which is anEBM-produced surface that was subject to HIP and mechanical and chemicalerosion;

FIG. 1C shows SEM images of additively manufactured surfaces, includingsurface 20C which is a DMLS-produced surface that was subject to HIP butno erosion and surface 22C which is a DMLS-produced surface that wassubject to HIP and mechanical and chemical erosion;

FIG. 1D shows SEM images of additively manufactured surfaces, includingsurface 16E which is a laser-produced surface that was subject to hotisostatic pressing and mechanical erosion using a sodium bicarbonateblast and surface 16F which is a laser-produced surface that was subjectto hot isostatic pressing and mechanical erosion using a titanium blast;

FIG. 1E shows SEM images of additively manufactured surface 29D, whichis a laser-produced surface with a built-in macro texture that wassubject to hot isostatic pressing and mechanical and chemical erosion;

FIG. 2A shows the levels of alkaline phosphatase expressed by MG63 cellscultured on additively manufactured surfaces 20A, 20B, and 20C and 22A,22B, and 22C (surfaces 20A, 20B, and 20C and 22A, 22B, and 22C are thesame surfaces as described in FIGS. 1A, 1B, and 1C);

FIG. 2B shows the level of osteopontin expressed by MG63 cells culturedon additively manufactured surfaces 20A, 20B, and 20C and 22A, 22B, and22C (surfaces 20A, 20B, and 20C and 22A, 22B, and 22C are the samesurfaces as described in FIGS. 1A, 1B, and 1C);

FIG. 2C shows the level of RunX2 expressed by MG63 cells cultured onadditively manufactured surfaces 20A, 20B, and 20C and 22A, 22B, and 22C(surfaces 20A, 20B, and 20C and 22A, 22B, and 22C are the same surfacesas described in FIGS. 1A, 1B, and 1C);

FIG. 3A shows the levels of alkaline phosphatase expressed by SAOS-2cells cultured on additively manufactured surfaces 20A, 20B, and 20C and22A, 22B, and 22C (surfaces 20A, 20B, and 20C and 22A, 22B, and 22C arethe same surfaces as described in FIGS. 1A, 1B, and 1C);

FIG. 3B shows the levels of osterix expressed by SAOS-2 cells culturedon additively manufactured surfaces 20A, 20B, and 20C and 22A, 22B, and22C (surfaces 20A, 20B, and 20C and 22A, 22B, and 22C are the samesurfaces as described in FIGS. 1A, 1B, and 1C);

FIG. 3C shows the levels of osteocalcin expressed by SAOS-2 cellscultured on additively manufactured surfaces 20A, 20B, and 20C and 22A,22B, and 22C (surfaces 20A, 20B, and 20C and 22A, 22B, and 22C are thesame surfaces as described in FIGS. 1A, 1B, and 1C);

FIG. 3D shows the levels of alkaline phosphatase (left-most bar),osterix (center bar), and osteocalcin (right-most bar) expressed bySAOS-2 cells cultured on additively manufactured surfaces 16E, 16F, and29D, respectively (surfaces 16E, 16F, and 29D are the same surfaces asdescribed in FIGS. 1D and 1E);

FIG. 4 shows the titanium microstructure, illustrating the differentalloy phases of titanium;

FIG. 5 represents a titanium-oxygen phase diagram;

FIG. 6 is a graph representing carbon, nitrogen, and oxygenconcentrations as a function of distance from the surface when airreacts with titanium during a heating process;

FIG. 7A is an optical micrograph of a metallographic section of atitanium disc off the EBM machine and subject to HIP;

FIG. 7B is an optical micrograph of a metallographic section of atitanium disc off the EBM machine and subject to both HIP and aconventional blast process;

FIG. 7C is an optical micrograph of a metallographic section of atitanium disc off the EBM machine and subject to both HIP and tomechanical and chemical erosion; and

FIG. 8 shows how mechanical erosion and the combination of mechanicaland chemical erosion can remove unsintered or partially sintered powderfrom the additive build.

DETAILED DESCRIPTION OF THE INVENTION

Various terms relating to aspects of the present invention are usedthroughout the specification and claims. Such terms are to be giventheir ordinary meaning in the art, unless otherwise indicated. Otherspecifically defined terms are to be construed in a manner consistentwith the definition provided herein.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless expressly stated otherwise.

The terms “subject” or “patient” are used interchangeably. A subject maybe any animal, including mammals such as companion animals, laboratoryanimals, and non-human primates. Human beings are preferred.

“Vertically” additively manufacturing an orthopedic implant means thatduring the additive manufacture process, the build begins with a surfaceof the implant that does not contact bone (e.g., a free surface), suchthat the bone-contacting surfaces result from one or more of the edgesof the additively-laid layers. By way of example, but not of limitation,if the top or bottom surfaces of an orthopedic implant are intended tocontact bone but sides of the implant are not intended to contact bone,then the build begins with one of the sides of the implant, and thebone-contacting top and bottom arise as the layers are deposited.Vertical additive manufacture stands in contrast to the more traditionalhorizontal additive manufacturing processes where the build begins witha bone-contacting surface. By way of example, but not of limitation, ifthe top or bottom surfaces of an orthopedic implant are intended tocontact bone but sides of the implant are not intended to contact bone,then with horizontal additive manufacturing, the build begins witheither of the bone-contacting top or bottom layers.

As used herein, a “bulk substrate” means an orthopedic implant, or aprecursor, exemplar, or archetype of an orthopedic implant such as apreform, blank, solid, cast of metal, wrought metal, block of metal,metal ingot, or bulk of metal, that is made without any additivemanufacturing.

As used herein, “osteoinduction” and “osteoinducting” refers to theinduction or initiation of osteogenesis, and includes the recruitment ofimmature mesenchymal stem cells to a processed (e.g., mechanicallyand/or chemically eroded) bone-contacting surface and/or to a processed(e.g., mechanically and/or chemically eroded) free surface of anorthopedic implant, followed by the phenotype progression anddifferentiation of these stem cells to a preosteoblast and the furtherphenotype progression and differentiation of a preosteoblast to anosteoblast. Such phenotype progression and differentiation arecharacterized by upregulation of alkaline phosphatase expression by themesenchymal stem cells, followed by upregulation of osterix as themesenchymal stem cell differentiates to a preosteoblast, and followed byupregulation of osteocalcin as the preosteoblast matures into anosteoblast.

“Osteogenesis” includes the formation and development of bone matrix.

As used herein, “free surfaces” are surfaces of orthopedic implants thatdo not directly contact bone at the time the implant is implanted withinthe body. Nevertheless, free surfaces that are processed to impart anosteoinducting roughness comprising micro-scale and nano-scalestructures may stimulate de novo bone growth such that after a period oftime following implantation and attendant bone growth out from the freesurfaces, the free surfaces contact bone. In some aspects, one or moreof the free surfaces of an orthopedic implant may contact a bone graftmaterial (e.g., synthetic, allograft, or autograft material), forexample, when the implant is implanted within the body. The practitionermay place a bone graft material in contact with one or more of the freesurfaces.

It has been observed in accordance with the invention that additivemanufacture of orthopedic implants followed by a combination ofmechanical and chemical erosion of the additively manufactured surfacesresults in such surfaces being able to stimulate preosteoblasts tomature into osteoblasts, and to stimulate preosteoblasts and osteoblaststo upregulate the expression of proteins that promote and support boneproduction. It was found that at least the amount of such proteins wassignificantly enhanced by these surfaces, and it is believed that therate of the expression of such proteins was also enhanced. It isbelieved that these surfaces are also able to stimulate mesenchymal stemcells to differentiate into preosteoblasts, and to upregulate theexpression of proteins that promote and support bone production.

Where integration of orthopedic implants with adjacent bone (e.g.,osseointegration) is a desired outcome, the upregulation of suchproteins means that the integration process in the body (e.g., betweensuch surfaces and the adjacent bone) will proceed rapidly and robustly.Accordingly, the invention features osteoinducting bone-contactingsurfaces for orthopedic implants that are produced according to aprocess that begins with additive manufacture of an orthopedic implantfollowed by treatment of the surfaces of the additively-produced implantthat are intended to facilitate new bone growth with eroding techniquesthat produce and/or enhance osteoinducting structural features of thesurfaces.

In general, the processes for producing osteoinduction-enhancingbone-contacting surfaces comprise first additively manufacturing anorthopedic implant, e.g., the implant body having the desired basicshape, configuration, and structural orientation for the particularlocation within the body where the implant is to be implanted and forthe particular corrective application intended for the implant, and thentreating one or more surfaces (e.g., either or both of bone-contactingand free surfaces) of the implant to remove alpha case and produce abone growth-enhancing bioactive surface topography. In some preferredaspects, the one or more bone-contacting surfaces produced by sequentialadditive manufacturing and subtractive eroding processes comprise anoverlapping macro-scale roughness, micro-scale roughness, and nano-scaleroughness. In some preferred aspects, the one or more free surfacesproduced by sequential additive manufacturing and subtractive erodingprocesses comprise an overlapping micro-scale roughness and nano-scaleroughness. Each roughness may comprise regular, irregular, orcombinations of regular and irregular structural features, e.g., themacro-scale roughness, micro-scale roughness, and nano-scale roughnessmay independently be regular, irregular, or both regular and irregularin terms of the structural arrangement of the surface.

Additive manufacturing processes produce surfaces that are generallymicroscopically smooth. Accordingly, it is preferred that the additivemanufacturing techniques used to produce the orthopedic implant impart amacro-scale roughness in at least the bone-contacting surfaces, althoughfree surfaces produced via the additive process may be rough or smoothto the touch. The macro-scale roughness comprises macro-scale structuralfeatures, which function to grip bone and inhibit movement of an implantonce implanted within the body. The shape, configuration, orientation,size, design and layout of the macro-scale features may be programmedinto the additive manufacture software.

Thus, in some aspects, the additive manufacturing of the orthopedicimplant includes the engineering and designing of the geometry,dimensions, and structural features of the implant body, via additivemanufacture. The implant body may comprise any suitable shape orgeometry, and any suitable number of sides and surfaces—includingbone-contacting surfaces and including free surfaces—which may depend,for example, on the particular shape and location of the site ofimplantation within the body. The implant may comprise flat, round,regular, and/or irregular surfaces. By way of example, but not oflimitation, the orthopedic implant may comprise a joint replacement(e.g., hip, knee, shoulder, elbow, ankle, wrist, jaw, etc.), a long orshort bone (or portion thereof) replacement, a skull or jaw bonereplacement, an implant intended to induce fusion or physical joining ofseparate bones (e.g., finger joints, ankle joints, vertebrae, or spinalmotion segment), an implant intended to fasten another implant to a bone(e.g., bone screws, pedicle screws, and fixation elements), an implantto facilitate rejoinder of broken bones, including bone screws,intramedullary nail, rods, and plates, etc., or any implant to replace,repair, brace, or supplement any bone in the body. In some aspects, theimplant comprises an implant for replacing an intervertebral disc, orfor replacing a spinal motion segment. In highly preferred aspects, theimplant is intended for integration with the surrounding bone. Implantengineering and design may be computer assisted.

In addition, the additive manufacturing also includes the engineeringand designing of the geometry, dimensions, and structural features ofthe macro-scale structural features or roughness to be imparted into thebone-contacting surfaces of the implant. The engineering may derive fromthe imaging/optical scanning of a macro-scale roughness from surfacesproduced by aggressively acid-etching a bulk substrate, with the imagedinformation imported into the additive manufacture program model.

The engineering of the macro-scale roughness may take into accountrational design of particular values for one or more of the roughnessparameters established by the International Organization forStandardization (ISO), e.g., ISO 468:1982. Such parameters include, butare not limited to, Rp (max height profile), Rv (max profile valleydepth), Rz (max height of the profile), Rc (mean height of the profile),Rt (total height of the profile), Ra (arithmetic mean deviation of theprofile), Rq (root mean square deviation of the profile), Rsk (skewnessof the profile), Rku (kurtosis of the profile), RSm (mean width of theprofile), RΔq (Root mean square slope of the profile), Rmr (materialratio of the profile), Rδc (profile section height difference), lp(sampling length-primary profile), lw (sampling length-wavinessprofile), lr (sampling length-roughness profile), ln (evaluationlength), Z(x) (ordinate value), dZ/dX (local slope), Zp (profile peakheight), Zv (profile valley depth), Zt (profile element height), Xs(profile element width), and Ml (material length of profile). Otherparameters may include Rsa (surface area increase), Rpc (peak counts), H(Swedish height), ISO flatness (areal flatness deviation), Pt ISO(peak-to-valley profile height), Rtm (mean peak-to-valley roughness), Rv(lowest value), Rvm (mean valley profile depth), Ry (maximumpeak-to-valley roughness), Rpm (mean peak areal height), S (averagespacing between local peaks), SM (average spacing between peaks at themean line), summit number, summit density, summit spacing, valleynumber, valley density, and valley spacing. Additionally, it iscontemplated that the additive manufacturing may further include theengineering and designing of the geometry, dimensions, and structuralfeatures of the micro-scale roughness and/or the nano-scale roughness tobe imparted into the bone-contacting or free surfaces of the implant,particularly as the capabilities of additive manufacturing equipmentevolve to allow for finer and more nuanced details to be additivelymanufactured.

The orthopedic implants may be additively manufactured from any suitablematerial, including a metal, a ceramic, bone, or any combination orcomposite thereof. Metals are highly preferred. Metals may comprise analloy. Preferred metals include titanium and titanium alloys such asnickel-titanium alloys (for example, nitinol), and aluminum and vanadium(e.g., 6-4) alloys of titanium, cobalt chromium alloys, as well assurgical grade steel (e.g., stainless steel). The orthopedic implantsare preferably not manufactured from polymers such as polyether etherketone (PEEK).

Additive manufacturing may comprise successively layering by depositingsolid material onto a substrate, then sintering or melting the depositedsolid material into a layer of the orthopedic implant, then depositingmore solid material onto the previous layer, then sintering or meltingthe newly deposited layer to both fuse with the previous layer andestablish the next layer, and repeating these steps until the implant iscompleted. The solid material being deposited may be in the form ofwires, powders, particles, granules, fragments, or combinations thereof,which is sintered or melted by an energy source. The powders, particles,granules, fragments, or combinations thereof preferably aresubstantially spherical in shape. It is preferred that the powders,particles, granules, fragments, or combinations thereof do not compriseirregular shapes or edges, or jagged edges. The spheres may comprisedifferent sizes, or may be substantially the same size.

The additive manufacturing may comprise sintering and/or melting of thepowders, particles, granules, wires, fragments, or combinations thereof.The sintering and/or melting preferably achieves substantially completemelting of the powders, particles, granules, fragments, or combinationsthereof such that the layer being deposited is comprised ofsubstantially fully molten material, the material preferably beingmetal. Suitable additive manufacturing techniques include, withoutlimitation, selective laser sintering, including, for example, directmetal laser sintering (DMLS) (DMLS® is a service mark of EOS GmbH),selective laser melting, including, for example, laserCUSING™ (ConceptLaser Schutzrechtsverwaltungs GmbH), electron beam melting (EBM), fuseddeposition modeling (FDM), direct metal deposition, laser Engineered NetShaping (LENS), and wire-based directed energy deposition. Thus, theenergy source may comprise a laser or an electron beam, although anysuitable technique for melting the material may be used.

Deposition and/or sintering or melting may take place in an inertenvironment, for example, with low oxygen and/or in the presence ofnitrogen and/or argon. In some aspects, a preceding layer (having justbeen formed) has not substantially solidified prior to the successivelayer being deposited thereon. In some aspects, a preceding layer(having just been formed) has at least partially solidified prior to thesuccessive layer being deposited thereon.

In some aspects, the implant is vertically additively manufactured. Thevertical additive manufacture begins by creating a layer that wouldconstitute a surface other than a bone-contacting surface of the implantbeing manufactured (e.g., a free surface), with successive layers beingdeposited and sintered or melted until the opposing face is completed.Bone-contacting surfaces thereby arise from the edges of the layers laidin a vertical build scheme.

Following completion of building the implant body through the additiveprocess, the implant body may be subject to stress-relieving processing,including a reheat of the formed implant body. Stress relief may becarried out under vacuum and/or an inert gas. The heating may occur attemperatures that cause diffusion within the metal, and then followed bya cooling step. In some aspects, the reheat may also be accompanied bypressure. The pressure may be either uniaxial (e.g., applied from onedirection; hot uniaxial pressing or HUP) or isostatic (e.g., appliedevenly from all directions). Hot isostatic pressing (HIP) is highlypreferred.

HIP is conducted by placing the implant body in a sealed container whichcan be heated and pressure controlled by adding and removing gases.Typically, once the implant body is placed in the sealed container, thecontainer is evacuated to remove any contaminating gasses. The containeris then heated while introducing an inert gas (for example, Argon) intothe chamber to increase the pressure. The container is then held at theelevated temperature and pressure for a period of time, after which thecontainer is rapidly cooled and depressurized.

HIP is conducted at a temperature below the melting point of thematerial from which the implant body is made, but at a sufficiently hightemperature where diffusion and plastic deformation of the implant bodyoccur. The temperature is typically less than 80% of the meltingtemperature. For example, for a titanium alloy including 6% aluminum and4% vanadium, the implant body may be heated to a temperature rangingfrom 895° C. (1,643° F.) to 955° C. (1,751° F.) ±15° C. (59° F.) at apressure of at least 100 MPa (14,504 PSI) for a period of 180±60 minutesand then cooled to below 425° C. (797° F.), according to ASTM StandardSpecification F3001. Similar specifications are known to one of ordinaryskill in the art for other materials, for example other standards fromASTM.

It is believed that HIP results in changes to the implant body. Forexample, the combination of temperature and pressure results in thecollapse of any inclusions present within the implant body. In someaspects, the density of the implant body may be substantially near orequal to 100% following HIP, meaning that the implant may besubstantially free of inclusion bodies (internal pores). Removinginter-layer boundaries and removing inclusions improve the mechanicalstrength of the implant body and reduce the likelihood of failure onceimplanted. Metal diffusion may also reduce or eliminate boundariesbetween metal layers resulting from the additive manufacturing processdescribed above.

In addition, the elevated temperature and pressure from HIP encouragesmetal diffusion across grain boundaries, resulting in a refinement ofthe grain structure, grain size, grain composition, grain distribution,or any combination thereof. In some aspects, HIP may increase at leastthe grain size, particularly when coupled to an electron beam meltingadditive build. HIP may change both the grain structure and theintergranular boundaries on the implant surfaces.

Following the additive manufacturing steps, and further followingstress-relief, HUP, or HIP treatments, if such treatments are employedin the process, the process further includes eroding the bone-contactingsurfaces, the free surfaces, or both the bone-contacting and freesurfaces that were additively produced to impart osteoinductingstructural features into these surfaces. The osteoinducting structuralfeatures include micro-scale structures and nano-scale structures thatpromote or enhance osteoinduction. One or more of the bone-contactingsurfaces of the additively manufactured implant are mechanically,chemically, or mechanically and chemically eroded to impart anosteoinducting roughness comprising micro-scale structures andnano-scale structures into the bone-contacting surfaces. In someaspects, one or more of the free surfaces of the additively manufacturedimplant are mechanically, chemically, or mechanically and chemicallyeroded to impart an osteoinducting roughness comprising micro-scalestructures and nano-scale structures into the free surfaces. Thus,either or both of bone-contacting and free surfaces of the additivelymanufactured implant may be processed to comprise osteoinductingmicro-scale and nano-scale structures. Effectively, such processing mayestablish an overlap of the macro-scale structures that were additivelymanufactured with the erosion-produced micro-scale and nano-scalestructures.

The mechanical and/or chemical treatments serve as a subtractiveprocess, for example, erosion or etching. Mechanical erosion includes,but is not limited to, exposure of bone-contacting surfaces of theorthopedic implant to photo etching, energy bombardment, plasma etching,laser etching, electrochemical etching, machining, drilling, grinding,peening, abrasive blasting (e.g., sand or grit blasting, includingblasting with aluminum or titanium oxide particles), or any combinationsof such processes. Chemical erosion may comprise, for example, exposureof select surfaces or the entire implant to a chemical such as an acidor a base, with the acid or base etching the bone-contacting surfacesthat come in contact with the acid or base. Chemical erosion mayinclude, but is not limited to, chemical, electrochemical,photochemical, photoelectrochemical, or other types of chemical milling,etching, or other treatments used to remove portions of the substrate.Etchants may be wet or dry, and any state: liquid, gas, or solid. Inpreferred aspects, mechanical erosion and chemical (e.g., acid) erosionare used successively following additive manufacturing. It is preferredthat mechanical erosion precedes the chemical erosion. Preferably,neither mechanical erosion nor chemical erosion introduces pores intothe bone-contacting surfaces.

Prior to erosion of implant surfaces for imparting osteoinductingfeatures into such surfaces, other surfaces of the implant that are notintended to be osteoinducting or otherwise induce bone growth, or whichhave been additively manufactured as smooth, may be protected bymasking. In some aspects, free surfaces may be protected by masking. Theexposed, non-masked surfaces of the implant may then be mechanically andchemically eroded.

Mechanical erosion is preferably achieved by blasting using particles.Particles may include organic or inorganic media. Suitable particlesinclude, for example, aluminum oxide particles and/or titanium oxideparticles and/or glass bead particles and/or pumice particles and/orsilicon carbide particles and/or hydroxyapatite particles, or othersuitable metal particles, or ceramic particles. Organic particles suchas walnut shells or dissolvable particles such as sodium bicarbonate arealso suitable.

Chemical erosion is preferably achieved using acids, although anychemicals capable of eroding a bone-contacting surface of the implantmaterials may be used. Preferred acids are strong acids such as HF,HNO₃, H₂SO₄, HCl, HBr, HI, HClO₄, citric acid, and any combinationthereof, although the particular acid used is not critical. It isbelieved that the acids etch the grain structures and grain boundariesin a way that enhances the osteoinduction-enhancing properties of thebone-contacting or free surfaces. It is highly preferred that thechemical erosion follows the mechanical erosion. Chemical erosion may becompleted in a single chemical treatment, although multiple treatmentsmay be employed in order to add or enhance the nano-scale structures onthe bone-contacting surfaces. Control of the strength of the chemicalerodent, the temperature at which the erosion takes place, and the timeallotted for the erosion process allows fine control over the resultingsurface produced by erosion.

One or both of the mechanical and chemical erosion processing stepsmight remove unwanted contaminants. In some applications, oxides thattend to form on metal surfaces can be removed. In other applications,however, oxides may be desirable and, therefore, the processing stepsshould be designed to avoid removing the oxides. More specifically, someoxide on titanium surfaces can be beneficial. See, for example, U.S.Patent Application Publication No. 2010/0174382 filed by Gretzer et al.Gretzer et al. disclose a bone tissue implant having an implant surface.The surface is covered by an oxide layer that includes strontium ions.The applicants assert that the strontium ions in the oxide layer have adesired osseoinductive effect.

In other applications, oxide on titanium surfaces must be avoided orremoved. It is especially desirable to avoid or remove a specificoxygen-enriched surface phase called “alpha case” on implants formed oftitanium or titanium alloys. One or a combination of the mechanical andchemical erosion processing steps discussed above may substantiallyremove alpha case, if present, from the eroded surfaces of a titaniumimplant. A discussion of such removal follows.

A. Alpha Case and its Titanium Basis

Titanium was discovered and named in 1791 and 1795, respectively.Although its impure form was first prepared in 1887, the pure metal(99.9%) was not made until 1910. Titanium is found in a number ofsources including meteorites, minerals, iron ores, the ash of coal,plants, and the human body. The method that is still largely used toproduce titanium commercially was discovered in 1946 and uses magnesiumto reduce titanium tetrachloride and isolate the pure metal.

Pure titanium is a lustrous, white metal. It has a relatively highmelting point of about 1,720° C. (3,140° F.), a low specific gravity of4.5, a low density, good strength, and excellent resistance to corrosionat temperatures below about 425-540° C. (800-1,000° F.). The modulus ofelasticity of titanium is 16×10⁶ lb/in², which means that it has greaterstiffness than most aluminum alloys. Titanium is easily fabricated.These properties make the use of titanium and its alloys veryattractive, and titanium is important as an alloying agent with othermetals. Alloys of titanium are used, for example, in medical implants.

Titanium metal and its alloys have the disadvantage of reacting withother elements at temperatures above about 425° C. (800° F.), whichrestricts its use at elevated temperatures. The reaction characteristicsof titanium at elevated temperatures cause considerable difficulties inprocessing operations as well as in its initial production.

Titanium exists in two allotropic forms: alpha at temperatures up to885° C. (1,625° F.) and beta above that temperature. Alpha titanium hasan hexagonal close packed (HCP) crystal structure while beta isbody-centered cubic (BCC). Most alloying elements decrease thealpha-to-beta transformation temperature. Oxygen, nitrogen, and aluminumraise the transformation temperature. Oxygen and nitrogen increasehardness and strength, however, with a decrease in ductility and, hence,formability. The stabilizing effect of aluminum on the alpha phasepromotes stability at higher temperatures, which makes aluminum animportant element in many of the titanium alloys.

The alloying elements iron, manganese, chromium, molybdenum, vanadium,columbium, and tantalum stabilize the beta phase, thus decreasing thealpha-beta transformation temperature. Additions of columbium andtantalum produce improved strength and help in preventing theembrittlement produced by the presence of compounds of titanium andaluminum. The elements nickel, copper, and silicon are activeeutectoid-formers, while manganese, chromium, and iron are sluggish inthe formation of a eutectoid. The elements tin and zirconium are solublein both the alpha and beta structures.

Titanium alloys can be classified into three general categoriesdepending upon the structures: (1) all-alpha alloys contain neutralalloying elements and/or alpha stabilizers only, are not responsive toheat treatment, and, hence, do not develop the strength possible inother alloys; (2) alpha-beta alloys contain a combination of alpha andbeta stabilizers, are heat treatable to various degrees, and have goodductility; and (3) all-beta alloys are metastable, have relatively lowductility, contain sufficient beta stabilizers to completely retain thebeta phase upon processing, and can be solution treated and aged toachieve significant increases in strength.

FIG. 4 shows an example of the titanium microstructure illustrating thedifferent alloy phases of titanium. Stabilizers are elements that havehigh solubility in metals and are typically used in alloys. The purposeof adding stabilizers to titanium is to alter the transformationtemperature of a specific phase to create a binary alpha-beta phase.Alpha stabilizers, typically aluminum, are added to raise thetransformation temperature of the alpha phase. Vanadium, an isomorphousbeta stabilizer, is completely soluble in the beta phase. Other betastabilizers such as iron are not completely soluble, which produceseutectoid phase. The stabilizers are represented in the name by theirperiodic table symbols and weight percent. For example, Ti-6Al-4V is 6%aluminum and 4% vanadium.

Ti-6Al-4V is the most common titanium alloy and accounts for more than50% of total titanium usage. It is an alpha-beta alloy, which is heattreatable to achieve moderate increases in strength. Ti-6Al-4V is aworld standard in many applications because it offers high strength,light weight, ductility, and corrosion resistance. One of the mostcommon applications of this alloy is medical devices.

ELI stands for extra low interstitials and is a higher-purity version ofTi-6Al-4V, with lower limits on iron and interstitial elements carbonand oxygen. Like Ti-6Al-4V, it is also an alpha-beta alloy. TI-6Al-4VELI has excellent biocompatibility, and therefore has been the materialof choice for many medical applications. It has superior damagetolerance (fracture toughness, fatigue crack growth rate) and bettermechanical properties at cryogenic temperatures when compared tostandard Ti-6AI-4V. Common applications for TI-6-4 ELI include jointreplacements, bone fixation devices, surgical clips, and cryogenicvessels.

B. Alpha Case

Titanium readily absorbs oxygen at high temperatures. When titanium andits alloys are exposed to heated air or oxygen, the formation of theoxygen-enriched surface phase called alpha case can occur. The alphacase layer is caused by oxygen diffusion into the titanium surface. Moregenerally, alpha case is the carbon, nitrogen, or especiallyoxygen-enriched alpha stabilized surface that is present on titaniumafter heating.

FIG. 5 represents a titanium-oxygen phase diagram. The HCP phaserepresents the alpha phase and BCC is the beta phase. The alpha-betaphase is the region between HCP and BCC. The line dividing the binaryphase from the HCP phase is the concentration of oxygen needed to formalpha case. Often, heat treatment processes reach temperatures on thephase diagram where this scenario is possible.

FIG. 6 is a graph representing carbon, nitrogen, and oxygenconcentrations as air reacts with titanium at the titanium surfaceduring a heating process. As expected, the carbon and nitrogenconcentrations are low and stable. The oxygen is much more soluble intitanium; therefore, its concentration gradient is much higher at thesurface. The values presented in the graph of FIG. 6 are subject toheating conditions, but the general behavior of oxygen, nitrogen, andcarbon is typical for titanium. The oxygen concentration gradientrepresents the alpha case phase described above. The thickness of thealpha case depends on the exposure time, atmosphere, and temperature.

Alpha case is undesirable because it is hard and brittle. Further, alphacase tends to create a series of micro-cracks which degrade theperformance of the titanium metal and, especially, its fatigue strengthproperties. Alpha case still further presents drawbacks against titaniumusage because alpha case can affect adversely corrosion resistance, andlimits the high temperature capability of titanium with respect tomechanical properties.

C. Forming Surfaces Free of Alpha Case

Given the disadvantages of alpha case, it is often desirable to formsurfaces of titanium implants that are free of alpha case. Generally,there are two ways to achieve such surfaces. One way is to avoid or atleast minimize the formation of alpha case in the first place (i.e.,during processing of the titanium). Formation of alpha case can beminimized by using vacuum metallurgy or an inert gas in which thetitanium is heated in the absence of oxygen. Thus, alpha case can beminimized or avoided by processing titanium at very deep vacuum levelsor in inert environments. For a variety of reasons, however, it may beimpractical or undesirable to process titanium in the absence of oxygen.

It is also possible to apply a coating to block carbon, nitrogen, andoxygen from the titanium surfaces being heated to control the formationof alpha case. The Ceram-Guard® line of coatings available from A.O.Smith Corporation may be suitable. The Ceram-Guard® coatings arehigh-temperature ceramic frits for temporarily coating and protectingmetal during heating. If no alpha case forms on the titanium surfaces,then there is no need to remove it.

Once present on the surface of titanium, however, the second way to formsurfaces of titanium implants that are free of alpha case is to removethe alpha case. Alpha case can be removed after heat treatmentmechanically or chemically. See, for example, European PatentApplication Publication No. 1947217 B1, titled “Method of removing analpha-case titanium layer from a beta-phase titanium alloy,” publishedon May 23, 2012 and assigned to United Technologies Corporation. Thepublished application discloses a method of surface treating a titaniumarticle that includes the step of chemically removing a surface layerhaving titanium alloy alpha-phase. In one disclosed example, thechemical removal includes using a first solution having nitric acid andhydrofluoric acid, and a second solution having nitric acid.

An emerging technique is to subject the titanium metal to anelectrochemical treatment in molten salts, such as calcium chloride orlithium chloride at elevated temperatures. This method is effective, atleast in laboratory settings, in removal of the dissolved oxygen fromthe alpha case, and hence recovery of the metal. Unfortunately, however,an unwanted consequence of the high temperature treatment is the growthof the grains in the metal. Grain growth may be limited by lowering themolten salt temperature. Alternatively, the metal may be furtherprocessed to break the large grains into smaller ones.

An important aspect of the processes used to form implant surfaces thatenhance osteoinduction, according to the present invention and when theimplant is formed of titanium, is to remove any alpha case. The alphacase is removed by the subtractive processing steps of mechanicalerosion (e.g., machining), chemical erosion (e.g., etching or milling),or both. These steps are discussed above. The efficacy of suchsubtractive processing steps in removing alpha case is illustrated inFIGS. 7A, 7B, and 7C.

Alpha case is visible in a polished and etched micro-section as a whitelayer in an optical metallurgical microscope or a dark layer in ascanning electron microscope (SEM) in back-scatter mode. (A SEM is atype of microscope that produces images of a sample by scanning it witha focused beam of electrons.) Alpha case can also be detected bymicro-hardness indentation of a section normal to the surface.

Titanium discs were additively manufactured using electron beam melting(EBM). These discs were then subject to hot isostatic pressing (HIP).One of the discs received no further processing (FIG. 7A), another discwas blasted using a conventional process (FIG. 7B), and yet another discwas subject to mechanical and chemical erosion according to the processsteps discussed above. Optical micrographs of the discs were obtained,and are shown in FIGS. 7A, 7B, and 7C.

FIG. 7A is an optical micrograph of a metallographic section of atitanium disc off the EBM machine and subject to HIP. The disc exhibiteda lighter etching phase (area between two arrows) consistent with thepresence of alpha case, approximately 0.09 mm deep. FIG. 7B is anoptical micrograph of a metallographic section of a titanium disc offthe EBM machine and subject to both HIP and a conventional blastprocess. The disc exhibited a lighter etching phase (area between twoarrows) consistent with the presence of alpha case, approximately 0.015mm deep. FIG. 7C is an optical micrograph of a metallographic section ofa titanium disc off the EBM machine and subject to both HIP and tomechanical and chemical erosion according to the process steps discussedabove. The disc did not exhibit any lighter etching phase, indicatingthe absence of any alpha case.

Mechanical erosion, chemical erosion, and the combination of mechanicaland chemical erosion substantially removes alpha case, if present, fromthe eroded surfaces of the titanium implant. It is believed that thiserosion combination fully removes alpha case. Thus, bone-contacting andfree surfaces of the implant are preferably substantially free orcompletely free of alpha case in some aspects.

More generally, mechanical erosion, chemical erosion, and thecombination of mechanical and chemical erosion can remove other (besidesalpha case) unwanted contaminants (or debris) from the implant surfaces.FIG. 8 shows how mechanical erosion and the combination of mechanicaland chemical erosion can remove unsintered or partially sintered powderfrom the additive build. FIG. 8 shows SEM images of a surface of asintered titanium alloy at 250× magnification (top row) and at 1,500×magnification (bottom row). The left column images show the magnifiedsurface off the machine (as additively built) without any follow-uperosion processing. The center column images show the magnified surfacefollowing mechanical erosion after the additive build. The right columnimages show the magnified surface following sequential mechanicalerosion and chemical erosion after the additive build.

In addition to imparting micro-scale structural features, mechanicaleroding may also remove or reduce debris from the implant surfaces. Acideroding may also remove or reduce debris from the implant surfaces inaddition to imparting nano-scale structural features into implantsurfaces. Debris may include external debris such as dirt or otherartifacts of handling. External debris may also include particles orcomponents of the media from the mechanical eroding/blasting step, whichparticles may have become lodged into the implant surface. Debris mayalso include intrinsic debris, such as artifacts of the additive buildprocess, for example, powder, particles, granules, etc. that were notcompletely melted or completely sintered during the additive building.

For example, FIG. 8 shows SEM images of a titanium surface created fromadditive building, with the images in the left column (at two differentmagnifications) illustrating that some particles have not fullyintegrated from the additive build. Thus, there is a risk that suchparticles on an implant may dislodge following implantation, and createnegative consequences for the patient either locally or systemically.The erosion process thus may be used to remove unsintered/unmelted orincompletely sintered or melted particles from the surfaces, therebyreducing the risk of particle dislodgement.

As shown in the center column of FIG. 8 , mechanical erosion cansignificantly reduce the amount of un-integrated or partially integratedparticles from the surface of the additively built structure. And asshown in the right column of FIG. 8 , the addition of chemical erosion(following mechanical erosion) can further reduce the amount ofun-integrated or partially integrated particles from the surface of theadditively built structure.

After the erosion process step or steps, any protective masking may beremoved from the implant, and the eroded and non-eroded surfaces may becleaned. The surface may also be passivated, for example, using anaqueous solution comprising nitric acid. The surface may be cleaned andrinsed with water.

In preferred aspects, no materials are added onto, impregnated into,embedded into, coated onto, sprayed onto, or otherwise placed on thebone-contacting surfaces. In preferred aspects, no materials are addedonto, impregnated into, embedded into, coated onto, sprayed onto, orotherwise placed on the free surfaces. (In fact, the erosion process maybe used to remove unwanted contaminants.)

Bone-contacting surfaces and free surfaces that have been produced byadditive manufacturing, followed by mechanical erosion, chemicalerosion, or both mechanical and chemical erosion comprise anosteoinducting roughness comprising a combination of macro-scale,micro-scale, and nano-scale structures. The additive manufacturingprocess preferably primarily produces macro-scale features that arespecifically engineered into the bone-contacting surfaces being producedduring the manufacturing, and the free surfaces produced from theadditive manufacturing process are substantially smooth and withoutthese macro-scale structures. Nevertheless, in some aspects, one or moreof the free surfaces may comprise macro-scale features, particularly,but not necessarily, when such surfaces are placed in contact with abone graft material upon implantation. The mechanical and chemicalerosion add the micro-scale and nano-scale structures, respectively, tothe processed bone-contacting surfaces and to the processed freesurfaces. In preferred aspects, mechanical erosion imparts primarily themicro-scale structures into the processed surfaces, and chemical erosionthat follows mechanical erosion imparts primarily the nano-scalestructures. The bone-contacting surfaces and free surfaces resultingfrom additive manufacture and mechanical and/or chemical erosion thusinclude a macro-scale roughness, a micro-scale roughness, and anano-scale roughness, which may at least partially overlap, or which maysubstantially overlap, or which may completely overlap. Collectively,these three scales of structural features significantly enhance one ormore of stem cell differentiation, preosteoblast maturation, osteoblastdevelopment, osteoinduction, and osteogenesis.

Macro-scale structural features include relatively large dimensions, forexample, dimensions measured in millimeters (mm), e.g., 1 mm or greater.Micro-scale structural features include dimensions that are measured inmicrons (μm), e.g., 1 micron or greater, but less than 1 mm. Nano-scalestructural features include dimensions that are measured in nanometers(nm), e.g., 1 nanometer or greater, but less than 1 micron. Patterns ofmacro structural features, micro structural features, and/or nanostructural features may be organized in regular and/or repeatingpatterns and optionally may overlap each other, or such features may bein irregular or random patterns, or repeating irregular patterns (e.g.,a grid of irregular patterns).

The additive manufacture and mechanical and chemical erosion stepsdescribed herein can be modulated to create a mixture of depths,heights, lengths, widths, diameters, feature sizes, and other geometriessuitable for a particular implant application. The orientation of thepattern of features can also be adjusted. Such flexibility is desirable,especially because the ultimate pattern of the osteoinduction-enhancingsurfaces may be oriented in opposition to the biologic forces that maybe applied against the implant upon implantation, and to theimplantation direction.

The macro-scale structural features, micro-scale structural features,and nano-scale structural features are distinct from teeth, spikes,ridges, and other bone-gripping super-macro scale structures that aretypically present on the surface of bone-contacting implants. Suchteeth, spikes, and ridges are intended to dig into or rake bone. Incontrast, the bone-contacting surfaces comprising macro structures asdescribed or exemplified herein, which are produced by additivemanufacturing, do not damage or dig into bone as teeth, spikes, ridges,and other bone-gripping super-macro scale structures do. Instead, thebone-contacting surfaces of the invention support a friction-type gripof bone surfaces and inhibit movement of the implant once implantedwithin the body.

The osteoinducting micro-scale and nano-scale structures onbone-contacting surfaces and on free surfaces produced by mechanicalerosion and chemical erosion after additive manufacture enhance and/orfacilitate osteoinduction. Additive manufacture followed by mechanicalerosion, chemical erosion, or both mechanical and chemical erosionproduces or imparts an osteoinducting roughness into bone-contacting andfree surfaces that are processed with such erosion. The osteoinductingroughness comprises micro-scale structures and nano-scale structuresthat combine to promote, enhance, or facilitate the rate and/or theamount of osteoinduction. From this osteoinducting roughness, new bonegrowth originates from and grows on and out from such processed surfacesof an orthopedic implant. The macro-scale structures on thebone-contacting surfaces of the orthopedic implant grip bone and inhibitmovement of the implant within the body and this, in turn, furtherpromotes, enhances, or facilitates the rate and/or the amount ofosteoinduction because movement inhibition inhibits the breaking of theincipient bone tissue as the new bone growth proceeds (e.g., unintendedmovement can disrupt the bone growth process by breaking newly formedbone matrix and tissue).

The enhancement and/or facilitation of osteoinduction from thebone-contacting surfaces and frees surfaces produced by additivemanufacture followed by mechanical erosion, chemical erosion, or bothmechanical and chemical erosion to impart an osteoinducting roughness issignificantly greater than the osteoinduction or the level ofenhancement and/or facilitation of osteoinduction that is attained by asurface that has not been subject to either or both of mechanical andchemical erosion. Bone-contacting and/or free surfaces that have notbeen subject to either or both of mechanical and chemical erosion may bedevoid of an osteoinducting roughness comprising micro-scale structuresand nano-scale structures. In some aspects, the one or morebone-contacting surfaces produced according to the process (additivemanufacture followed by mechanical and/or chemical erosion), when placedin contact with bone, significantly enhance one or more ofosteoinduction, osteogenesis, alkaline phosphatase expression bymesenchymal stem cells, osterix expression by preosteoblasts, andosteocalcin expression by osteoblasts, relative to the osteoinduction,osteogenesis, alkaline phosphatase expression by mesenchymal stem cells,osterix expression by preosteoblasts, and/or osteocalcin expression byosteoblasts from an untreated bone-contacting surface (not treated withmechanical and/or chemical erosion), when the untreated surface isplaced in contact with bone.

The enhancement and/or facilitation of osteoinduction from thebone-contacting surfaces and frees surfaces produced by additivemanufacture followed by mechanical erosion, chemical erosion, or bothmechanical and chemical erosion to impart an osteoinducting roughness issignificantly greater than the osteoinduction or the level ofenhancement and/or facilitation of osteoinduction that is attained by acomparative surface comprising an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures produced by mechanicalerosion, chemical erosion, or both mechanical and chemical erosion of abulk substrate (i.e., a substrate not produced by additive manufacture).Thus, when an implant is additively manufactured and its surfacesprocessed/eroded and when a comparative implant is manufactured from abulk substrate and its surfaces processed/eroded, the osteoinductionfrom the processed additively manufactured implant may be significantlyenhanced over the osteoinduction from the processed bulk substrate.

It is believed that orthopedic implant surfaces that are smooth, orcomprise teeth, ridges, grooves, and super-macro structures that are notprocessed/eroded, or comprise particles, fibers, or powders that havebeen cold sprayed, thermal sprayed, or affixed with an adhesive thereto,or which otherwise have not been mechanically eroded, chemically eroded,or both mechanically and chemical eroded to impart an osteoinductingroughness comprising micro-scale structures and nano-scale structures,or which otherwise lack an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures do not significantlyenhance osteoinduction, are not osteoinducting, and/or are inferior intheir osteoinduction capacity relative to orthopedic implant surfacesproduced by additive manufacture followed by mechanical erosion,chemical erosion, or both mechanical and chemical erosion to impart anosteoinducting roughness per the invention. Relatedly, orthopedicimplant surfaces that are smooth, or comprise teeth, ridges, grooves,and super-macro structures that are not processed/eroded, or compriseparticles, fibers, or powders that have been cold sprayed, thermalsprayed, or affixed with an adhesive thereto, or which otherwise havenot been mechanically eroded, chemically eroded, or both mechanicallyand chemical eroded to impart an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures, or which otherwiselack an osteoinducting roughness comprising micro-scale structures andnano-scale structures do not significantly enhance osteoinduction, arenot osteoinducting, and/or are inferior in their osteoinduction capacityrelative to orthopedic implant surfaces produced by mechanical erosion,chemical erosion, or both mechanical and chemical erosion of a bulksubstrate.

The osteoinducting micro-scale and nano-scale structures onbone-contacting surfaces and on free surfaces produced by mechanicalerosion and chemical erosion after additive manufacture enhance and/orfacilitate osteogenesis. Additive manufacture followed by mechanicalerosion, chemical erosion, or both mechanical and chemical erosionproduces or imparts an osteoinducting roughness into bone-contacting andfree surfaces that are processed with such erosion. The osteoinductingroughness comprises micro-scale structures and nano-scale structuresthat combine to promote, enhance, or facilitate the rate and/or theamount of osteogenesis. From this osteoinducting roughness, new bonegrowth originates from and grows on and out from such processed surfacesof an orthopedic implant. The macro-scale structures on thebone-contacting surfaces of the orthopedic implant grip bone and inhibitmovement of the implant within the body and this, in turn, furtherpromotes, enhances, or facilitates the rate and/or the amount ofosteogenesis because movement inhibition inhibits the breaking of theincipient bone tissue as the new bone growth proceeds (e.g., unintendedmovement can disrupt the bone growth process by breaking newly formedbone matrix and tissue).

The enhancement and/or facilitation of osteogenesis from thebone-contacting surfaces and free surfaces produced by additivemanufacture followed by mechanical erosion, chemical erosion, or bothmechanical and chemical erosion to impart an osteoinducting roughness issignificantly greater than the osteogenesis or the level of enhancementand/or facilitation of osteogenesis that is attained by a comparativesurface comprising an osteoinducting roughness comprising micro-scalestructures and nano-scale structures produced by mechanical erosion,chemical erosion, or both mechanical and chemical erosion of a bulksubstrate. Thus, when an implant is additively manufactured and itssurfaces processed/eroded and when a comparative implant is manufacturedfrom a bulk substrate and its surfaces processed/eroded, theosteogenesis from the processed additively manufactured implant may besignificantly enhanced over the osteogenesis from the processed bulksubstrate.

It is believed that orthopedic implant surfaces that are smooth, orcomprise teeth, ridges, grooves, and super-macro structures that are notprocessed/eroded, or comprise particles, fibers, or powders that havebeen cold sprayed, thermal sprayed, or affixed with an adhesive thereto,or which otherwise have not been mechanically eroded, chemically eroded,or both mechanically and chemical eroded to impart an osteoinductingroughness comprising micro-scale structures and nano-scale structures,or which otherwise lack an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures do not significantlyenhance osteogenesis, are not osteogeneic, and/or are inferior in theirosteogenesis capacity relative to orthopedic implant surfaces producedby additive manufacture followed by mechanical erosion, chemicalerosion, or both mechanical and chemical erosion to impart anosteoinducting roughness per the invention. Relatedly, orthopedicimplant surfaces that are smooth, or comprise teeth, ridges, grooves,and super-macro structures that are not processed/eroded, or compriseparticles, fibers, or powders that have been cold sprayed, thermalsprayed, or affixed with an adhesive thereto, or which otherwise havenot been mechanically eroded, chemically eroded, or both mechanicallyand chemical eroded to impart an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures, or which otherwiselack an osteoinducting roughness comprising micro-scale structures andnano-scale structures do not significantly enhance osteogenesis, are notosteogeneic, and/or are inferior in their osteogenesis capacity relativeto orthopedic implant surfaces produced by mechanical erosion, chemicalerosion, or both mechanical and chemical erosion of a bulk substrate.

Osteoinduction may be measured as a function of the level of one or moreof alkaline phosphatase (ALP) expression, osterix (OSX) expression, andosteocalcin (OXN) expression. These markers demonstrate the phenotypeprogression that confirms osteoinduction is occurring. ALP represents anearly marker of stem cell differentiation into a preosteoblast. Osterixrepresents the first bone-specific transcription factor expression(Runx2 is often considered the first transcription factor expressed as apart of the osteoblast differentiation process, although thistranscription factor is not specific to bone and influences otherbiochemical processes within the cell). Osteocalcin represents a matureosteoblast marker. In preferred aspects, the bone-contacting surfacesand free surfaces resulting from additive manufacture, mechanicalerosion, and chemical erosion significantly enhance and/or facilitateALP expression, then osterix expression, and then osteocalcin expressionfrom a stem cell as it differentiates to a preosteoblast and matures toan osteoblast.

Thus, where an implant was additively manufactured and its surfacesprocessed/eroded and where a comparative implant was manufactured from abulk substrate and its surfaces processed/eroded, the expression of oneor more of ALP, OSX, and OCN from mesenchymal stem cells,preosteoblasts, and osteoblasts, respectively, that have contacted theprocessed additively manufactured implant surfaces may be significantlyenhanced over the expression of one or more of ALP, OSX, and OCN frommesenchymal stem cells, preosteoblasts, and osteoblasts, respectively,that have contacted the processed bulk substrate surfaces.

It is believed that orthopedic implants whose surfaces do not have anosteoinducting roughness comprising micro-scale structures andnano-scale structures produced by mechanical erosion, chemical erosion,or both mechanical and chemical erosion, induce minimal expression ofone or more of ALP, OSX, and OCN from mesenchymal stem cells,preosteoblasts, and osteoblasts, respectively, or do not induceexpression of one or more of ALP, OSX, and OCN from mesenchymal stemcells, preosteoblasts, and osteoblasts, respectively, at all. Thus,orthopedic implant surfaces that are smooth, or comprise teeth, ridges,grooves, and super-macro structures that are not processed/eroded, orcomprise particles, fibers, or powders that have been cold sprayed,thermal sprayed, or affixed with an adhesive thereto, or which otherwisehave not been mechanically eroded, chemically eroded, or bothmechanically and chemical eroded to impart an osteoinducting roughnesscomprising micro-scale structures and nano-scale structures, or whichotherwise lack an osteoinducting roughness comprising micro-scalestructures and nano-scale structures do not significantly enhance theexpression of one or more of ALP, OSX, and OCN from mesenchymal stemcells, preosteoblasts, and osteoblasts, respectively, do not induceexpression of one or more of ALP, OSX, and OCN from mesenchymal stemcells, preosteoblasts, and osteoblasts, respectively, and/or areinferior in their capacity to induce expression of one or more of ALP,OSX, and OCN from mesenchymal stem cells, preosteoblasts, andosteoblasts, respectively, relative to orthopedic implant surfacesproduced by additive manufacture followed by mechanical erosion,chemical erosion, or both mechanical and chemical erosion to impart anosteoinducting roughness per the invention. Relatedly, orthopedicimplant surfaces that are smooth, or comprise teeth, ridges, grooves,and super-macro structures that are not processed/eroded, or compriseparticles, fibers, or powders that have been cold sprayed, thermalsprayed, or affixed with an adhesive thereto, or which otherwise havenot been mechanically eroded, chemically eroded, or both mechanicallyand chemical eroded to impart an osteoinducting roughness comprisingmicro-scale structures and nano-scale structures, or which otherwiselack an osteoinducting roughness comprising micro-scale structures andnano-scale structures do not significantly enhance the expression of oneor more of ALP, OSX, and OCN from mesenchymal stem cells,preosteoblasts, and osteoblasts, respectively, do not induce theexpression of one or more of ALP, OSX, and OCN from mesenchymal stemcells, preosteoblasts, and osteoblasts, respectively, and/or areinferior in their capacity to induce expression of one or more of ALP,OSX, and OCN from mesenchymal stem cells, preosteoblasts, andosteoblasts, respectively, relative to orthopedic implant surfacesproduced by mechanical erosion, chemical erosion, or both mechanical andchemical erosion of a bulk substrate.

The following examples are included to more clearly demonstrate theoverall nature of the invention. These examples are exemplary, notrestrictive, of the invention.

Example 1 SEM Images of Additively Manufactured Titanium Surfaces

Titanium discs were additively manufactured using either lasermelting/sintering (e.g., direct metal laser sintering (DMLS)) orelectron beam melting (EBM). These discs were then subject to eitherstress-relief or hot isostatic pressing, and were subject to mechanicaland chemical erosion as summarized in Table 1. Scanning electronmicroscope (SEM) images of the discs were obtained, and are shown inFIGS. 1A, 1B, 1C, 1D, and 1E. (A SEM is an electron microscope in whichthe surface of a specimen is scanned by a beam of electrons that arereflected to form an image.)

Surface 20A was a DMLS-produced surface that was subject tostress-relief, but no erosion. Surface 20B was an EBM-produced surfacethat was subject to hot isostatic pressing, but no erosion. Surface 20Cwas a DMLS-produced surface that was subject to hot isostatic pressing,but no erosion. Surface 22A was a DMLS-produced surface that was subjectto stress-relief and mechanical and chemical erosion. Surface 22B was anEBM-produced surface that was subject to hot isostatic pressing andmechanical and chemical erosion. Surface 22C was a DMLS-produced surfacethat was subject to hot isostatic pressing and mechanical and chemicalerosion.

Surface 16E was a laser-produced surface that was subject to hotisostatic pressing and mechanical erosion using a sodium bicarbonateblast. Surface 16F was a laser-produced surface that was subject to hotisostatic pressing and mechanical erosion using a titanium blast.Surface 29D was a laser-produced surface with a built-in macro texturethat was subject to hot isostatic pressing and mechanical and chemicalerosion.

The SEM images of FIGS. 1A, 1B, 1C, 1D, and 1E show how micro-scale andnano-scale structures are imparted into the titanium surface via thesuccessive mechanical and chemical erosion of the additivelymanufactured surfaces.

TABLE 1 Additively manufactured surfaces Post-additive #, Manufacturemanufacture treatment 20A, DMLS only Stress-relief 20B, EBM only HIP20C, DMLS only HIP 22A, DMLS followed by mechanical and Stress-reliefchemical erosion 22B, EBM followed by mechanical and HIP chemicalerosion 22C DMLS followed by mechanical and HIP chemical erosion 16E,laser-produced followed by mechanical HIP erosion 16F, laser-producedfollowed by mechanical HIP erosion 29D, laser-produced followed bymechanical HIP and chemical erosion

Example 2 Alkaline Phosphatase, Osterix, and Osteocalcin as RecognizedMarkers of Osteoblast Development and Osteoinduction

Osteogenic differentiation is a continuous process characterized by therise and fall of several proteins. The proteins analyzed hereincharacterize early (ALP), mid (OSX) and late (OCN) osteoblast markers.The process of osteoblast differentiation begins with mesenchymal stemcells progressing to an intermediate progenitor capable of undergoingeither osteogenesis or chondrogenesis and expressing ALP. Theseintermediate progenitors that commit to an osteogenic lineage, nowtermed preosteoblasts, increase the expression of ALP. As thepreosteoblast progresses to an osteoblast, the expression of OSX isincreased and, finally, once the preosteoblast becomes an osteoblast theexpression of OCN is increased.

The osteoblast will eventually mature further and begin transitioning toan osteocyte or undergoing apoptosis. The mature osteoblast state ischaracterized by a decrease in ALP, and once the osteoblastdifferentiates to an osteocyte the expression of both OSX and OCN isdecreased as well (Baek W-Y et al., J. Bone Miner. Res. 24:1055-65(2009); Zhang C., J. Orthopaedic Surg. and Res. 5:1 (2010); and Tu Q etal., Tissue Eng'g 1:2431-40 (2007)). In vivo evaluations have revealedthat both ALP and OCN are present during fracture healing. In theseevaluations, both ALP and OCN production are highest in healing bonefractures at 8 weeks post fracture (Leung K S et al., Bone & JointJournal 75:288-92 (1993); and Herrmann M. et al., Clin. Chemistry48:2263-66 (2002)). Furthermore, ALP and OCN have been used for in vitroevaluation of the potential for a synthetic material to promote boneformation in vivo. It has been further demonstrated that increased ALPand OCN in vitro associate with synthetic graft success in vivo (BordenM. et al., J. Biomed. Mater. Res. 61:421-29 (2002); Borden M. et al.,Biomaterials. 23:551-59 (2002); and Borden M. et al., J. Bone JointSurg. Br. 86:1200-08 (2004)). Similar evaluations using titanium meshhave correlated in vitro ALP and osteopontin (a matrix protein secretedearlier in differentiation than OCN) with in vivo success (Datta N.,Biomaterials. 26:971-77 (2005); Bancroft G. N., Proc. Natl. Acad. Sci.U.S.A. 99:12600-05 (2002); and Sikavitsas V I et al., J. Biomed. Mater.67A:944-51 (2003)).

Example 3 Assessment of Osteogenic Markers on MG63 Cells Grown onOsteoinductive Surfaces

MG63 cells are a preosteoblast cell line. MG63 cells were seeded ontodiscs at 10,000 cells/cm² cultured in EMEM with 10% FBS, 1%Penicillin/Streptomycin, 50 μg/mL Ascorbic Acid, and 10 mMβ-Glycerophosphate. After 7 days of culture, the cells were lysed with aPierce Mammalian Protein Extraction Reagent with protease inhibitors,and lysates were assessed for the expression of alkaline phosphatase(ALP), osteopontin (OPN), and RunX2. Alkaline phosphatase (ALP), anearly osteoblast differentiation marker, was measured through anenzymatic assay relying on the conversion of p-Nitrophenyl phosphate top-Nitrophenol in the presence of ALP and then measuring the absorbanceof p-Nitrophenol. ALP was normalized to the amount of DNA present in thesamples. DNA was measured with a standard PicoGreen assay. Osteopontin(OPN), a protein expressed by osteoblasts throughout differentiation,was measured through quantitative Western blotting and normalized totubulin. The results are shown in FIGS. 2A, 2B, and 2C. The surface keyfor FIGS. 2A-2C is shown in Table 1.

FIG. 2A shows the levels of alkaline phosphatase expressed by MG63 cellscultured on additively manufactured surfaces 20A, 20B, and 20C and 22A,22B, and 22C. FIG. 2B shows the level of osteopontin expressed by MG63cells cultured on additively manufactured surfaces 20A, 20B, and 20C and22A, 22B, and 22C. FIG. 2C shows the level of RunX2 expressed by MG63cells cultured on additively manufactured surfaces 20A, 20B, and 20C and22A, 22B, and 22C. Surfaces 20A, 20B, and 20C and 22A, 22B, and 22C arethe same surfaces as described in FIGS. 1A, 1B, and 1C.

As shown, the additively manufactured (DMLS and EBM) and processed(mechanically and chemically eroded) surfaces were significantly betterthan additively manufactured but not processed surfaces in terms of ALP,RunX2, and OPN expression.

Example 4 Assessment of Osteogenic Markers on SaOS-2 Cells Grown onOsteoinductive Surfaces

SAOS-2 cells were obtained from ATCC (Manassas, VA); PicoGreen Assays,McCoy's 5A media and Penicillin/Streptomycin were all obtained from LifeTechnologies (Carlsbad, CA); fetal bovine serum was obtained fromAtlanta Biologicals (Atlanta, GA); alkaline phosphatase assay wasobtained from Bio-Rad (Hercules, CA); Osterix ELISA was obtained fromLifeSpan BioSciences (Seattle, WA); and Osteocalcin ELSIA was obtainedfrom R&D Systems (Minneapolis, MN).

SAOS-2 cells were maintained in basal growth media consisting of McCoy's5A supplemented with 15% FBS and 1% Penicillin/Streptomycin. Onceappropriate numbers of cells were reached in culture, the SAOS-2 cellswere seeded on titanium disc surfaces (Table 1) at a density of 10,000cells/cm2. SAOS-2 cells were cultured on each surface type for sevendays, and media were changed every two days. At day 7, the media werefrozen for further analysis and the SAOS-2 cells were lysed in RIPAbuffer (150 mM sodium chloride, 1% v/v TRITON® X-100 non-ionicsurfactant, 0.5% w/v sodium deoxycholate, 0.1% w/v sodium dodecylsulfate, 50 mM Trizma base, pH 8.0).

Cellular DNA was quantified using a PicoGreen Assay following themanufacturer's protocol. Alkaline phosphatase (ALP) was assayed throughthe ALP catalyzed conversion of p-nitrophenylphosphate to p-nitrophenolfollowing the manufacturer's protocol. Both osterix (OSX) andosteocalcin (OCN) were quantified using and ELISA assay and followingthe manufacturer's protocol. Runx2 and OPN were also assayed, butneither demonstrated any substantial trend or significant data (data notshown); these are both very early osteoblast markers. The results areshown in FIGS. 3A, 3B, 3C, and 3D. The surface key for FIGS. 3A-3D isshown in Table 1.

FIG. 3A shows the levels of alkaline phosphatase expressed by SAOS-2cells cultured on additively manufactured surfaces 20A, 20B, and 20C and22A, 22B, and 22C. FIG. 3B shows the levels of osterix expressed bySAOS-2 cells cultured on additively manufactured surfaces 20A, 20B, and20C and 22A, 22B, and 22C. FIG. 3C shows the level of osteocalcinexpressed by SAOS-2 cells cultured on additively manufactured surfaces20A, 206, and 20C and 22A, 22B, and 22C. FIG. 3D shows the levels ofalkaline phosphatase (left-most bar), osterix (center bar), andosteocalcin (right-most bar) expressed by SAOS-2 cells cultured onadditively manufactured surfaces 16E, 16F, and 29D, respectively.Surfaces 20A, 20B, 20C, 22A, 22B, 22C, 16E, 16F, and 29D are the samesurfaces as described in FIGS. 1A, 1B, 1C, 1D, and 1E.

As shown in FIGS. 3A, 3B, and 3C, all additively manufactured andprocessed (mechanically and chemically eroded) surfaces demonstratedimproved expression of the ALP, OSX, and OCN markers relative tosurfaces that were additively manufactured without processing(mechanically and chemically erosion). Processing of additivelymanufactured surfaces significantly enhanced osteoblast differentiation,as demonstrated by the ALP, OSX, and OCN markers, relative to additivelymanufactured surfaces without erosion. As shown in FIG. 3D, theadditively manufactured and processed (mechanically and chemicallyeroded) surface 29D demonstrated improved expression of the ALP, OSX,and OCN markers relative to surfaces 16E and 16F that were additivelymanufactured and processed with only mechanical but not chemicalerosion.

Although illustrated and described above with reference to certainspecific embodiments and examples, the present invention is neverthelessnot intended to be limited to the details shown. Rather, variousmodifications may be made in the details within the scope and range ofequivalents of the claims and without departing from the spirit of theinvention. It is expressly intended, for example, that all rangesbroadly recited in this document include within their scope all narrowerranges which fall within the broader ranges. It is also expresslyintended that the steps of the processes of manufacturing the variousdevices disclosed above are not restricted to any particular orderunless specifically and otherwise stated.

What is claimed:
 1. An orthopedic implant having a titanium or titaniumalloy body with a plurality of surfaces, the orthopedic implant producedaccording to a process comprising the steps of: (a) additively buildingthe orthopedic implant; and then (b) mechanically, chemically, ormechanically and chemically eroding one or more surfaces of theorthopedic implant to (i) remove alpha case from, and (ii) impart anosteoinducting roughness including micro-scale structures and nano-scalestructures into, the one or more surfaces.
 2. The orthopedic implantaccording to claim 1, wherein the one or more surfaces include surfaceswithin the interior of the body of the orthopedic implant.
 3. Theorthopedic implant according to claim 1, wherein the one or moresurfaces contact bone or a bone graft material.
 4. The orthopedicimplant according to claim 1, wherein the one or more surfaces are freesurfaces.
 5. The orthopedic implant according to claim 1, wherein thestep (b) further comprises mechanically eroding the one or more surfacesof the orthopedic implant and, thereafter, chemically eroding the one ormore surfaces.
 6. The orthopedic implant according to claim 5, whereinmechanically eroding the one or more surfaces of the orthopedic implantimparts micro-scale structures into the one or more surfaces andchemically eroding the one or more surfaces of the orthopedic implantimparts nano-scale structures into the one or more surfaces.
 7. Theorthopedic implant according to claim 6, wherein the chemically erodednano-scale structures overlap with the mechanically eroded micro-scalestructures.
 8. The orthopedic implant according to claim 7, wherein thestep (a) of additively building the orthopedic implant yieldsmacro-scale structural features, which inhibit movement of theorthopedic implant, and the macro-scale structural features, themicro-scale structural features, and the nano-scale structural featuresoverlap each other.
 9. The orthopedic implant according to claim 1,wherein the process further comprises the step of treating theorthopedic implant with hot isostatic pressure or with hot uniaxialpressure or to relieve stress.
 10. The orthopedic implant according toclaim 9, wherein the treating step is completed under vacuum or in aninert gas.
 11. The orthopedic implant according to claim 1, wherein theprocess further comprises the step of applying a coating to theadditively built orthopedic implant, before further processing, to blockcarbon, nitrogen, and oxygen from the one or more surfaces to be furtherprocessed.
 12. The orthopedic implant according to claim 1, wherein thestep (a) of additively building the orthopedic implant is completed bymelting powder, particles, granules, wires, fragments, or combinationsthereof of the titanium or titanium alloy into the shape of theorthopedic implant.
 13. The orthopedic implant according to claim 1,wherein the step (a) of additively building the orthopedic implant iscompleted by sintering powder, particles, granules, wires, fragments, orcombinations thereof of the titanium or titanium alloy into the shape ofthe orthopedic implant.
 14. The orthopedic implant according to claim 1,wherein the step (a) of additively building the orthopedic implantcomprises vertically additively building the orthopedic implant.
 15. Anorthopedic implant having a titanium or titanium alloy body with aplurality of surfaces, the orthopedic implant produced according to aprocess comprising the steps of: (a) additively building the orthopedicimplant having one or more free surfaces and having one or morebone-contacting surfaces adapted to be placed in contact with bone, atleast the one or more bone-contacting surfaces having a macro-scaleroughness that inhibits movement of the orthopedic implant when thebone-contacting surfaces are placed in contact with bone; and then (b)sequentially mechanically and chemically eroding one or more of the oneor more free surfaces and the one or more bone-contacting surfaces to(i) remove alpha case from, and (ii) impart an osteoinducting roughnessincluding micro-scale structures and nano-scale structures into, one ormore of the one or more free surfaces and the one or morebone-contacting surfaces.
 16. The orthopedic implant according to claim15, wherein the macro-scale structural features, the micro-scalestructural features, and the nano-scale structural features overlap eachother.
 17. The orthopedic implant according to claim 15, wherein theprocess further comprises the step of treating the orthopedic implantwith hot isostatic pressure or with hot uniaxial pressure or to relievestress.
 18. The orthopedic implant according to claim 17, wherein thetreating step is completed under vacuum or in an inert gas.
 19. Theorthopedic implant according to claim 15, wherein the process furthercomprises the step of applying a coating to the additively builtorthopedic implant, after the step (a) and before further processing, toblock carbon, nitrogen, and oxygen from the one or more surfaces to befurther processed.
 20. The orthopedic implant according to claim 15,wherein the step (a) of additively building the orthopedic implant iscompleted by melting or sintering powder, particles, granules, wires,fragments, or combinations thereof of the titanium or titanium alloyinto the shape of the orthopedic implant.